Good morning. Welcome to the first day of the BofA Healthcare Conference. My name is Geoff Meacham. I'm the Senior Biopharma analyst, and we're thrilled to kick off this morning's session with Lyell Immunopharma. And so with me on stage, President and CEO Lynn Seely and also CFO Charlie Newton. So guys, welcome. Thank you. Thank you. We've got, you know, 15 minutes to do a quick Q&A here. So maybe, Lynn, just to give us kind of the 30,000-foot view for those on the webcast or in the audience that may not be as familiar with the story. Absolutely. Well, Geoff, I'm delighted to be here, and for those of you who don't know a lot about Lyell Immunopharma, we are an oncology company focused on delivering novel T cell therapies for patients suffering from solid tumor malignancies. We have two programs in the clinic, a CAR T cell program and a Tumor Infiltrating Lymphocyte or TIL program, both expected to have data this year. We also have a third program where we'll be filing the IND this quarter, so a lot of activity. And it's important to know that Lyell's programs are really focused on getting T cell function right. We want to enhance the patient's own extraordinary T cells to help them become better able to fight the cancers. To do this, we focus on two key barriers: T cell exhaustion and this ability to have durable stemness, or this ability to self-renew over time. So we have four technologies. They're platform technologies that we incorporate in various combinations in our clinical programs to help the T cells really gain that function. And all of our technologies are novel, they're proprietary, and we think give us a real advantage to get T cell therapy right in solid tumors. Lynn, in conjunction with the development of cell therapies, you also need manufacturing capabilities. Talk a little bit about how that differentiates Lyell from other, you know, cell therapy companies. Sure. It's a really important feature for Lyell. Charlie, you want to talk about our manufacturing? Yeah. So we do have our own manufacturing facility up in Bothell, Washington, which allows us to produce all of our cell products, both our TIL program, as well as both of our CAR programs, LYL797, that's in the clinic, and then LYL119, that is about to go into the clinic. So it provides us plenty of capacity to get through our clinical studies and frankly, even into early commercial launch. Right. Well, so on 797, and, it's a CAR T against ROR1, you guys are in the clinic, so maybe give us some sort of perspective on selection of the target and kind of what we should, you know, expect to see, you know, coming up as data mature? Sure. So this is a really important time for Lyell. We have our first ROR1 CAR T cell program in the clinic, and in fact, we have said we'll be presenting data this quarter, so coming very soon. The program is directed at ROR1, and in this particular program, we have overexpressed c-Jun, which is one of our technologies to help T cells resist exhaustion. And what we know is that when you overexpress c-Jun, that it potently enhances the AP-1 pathway, which has been shown in publications in multiple different models to help T cells resist exhaustion. And so this is a phase I trial where we are enrolling patients with triple-negative breast cancer and with non-small cell lung cancer. It's a standard dose escalation, dose expansion trial, and we'll be presenting data on about 20 patients here before the end of the quarter. Focused, of course, on this ability to see if we can help cells resist exhaustion, infiltrate into tumors and kill the cancer cells. So it'll be a nice data set where we'll be looking at clinical activity, safety, and we have a robust translational program as well. And just in that context, Lynn, when you look at the preclinical development on ROR1 to support the clinical program, talk about the metrics that you guys have looked at with respect to initial tumor antitumor activity, as well as the durability of the response, I guess, measured by T cell exhaustion. You can translate the animal data pretty straightforward into the concepts of what you're going to expect in the clinic. So, Lyell's program is really based on clinical data. There was a lovely, elegant experiment done at the Fred Hutch Cancer Center, where they really wanted to understand the difference between CAR T cells in hematologic malignancies and in solid tumors. And so they took a ROR1 construct, and they treated patients with chronic lymphocytic leukemia and got very nice results. The cells expanded, and they were able to successfully see responses in those patients. But they took the same ROR1 construct, and they put it in patients with solid tumors, triple-negative breast cancer and non-small cell lung cancer, ROR1-positive tumors, and they saw something different. The cells didn't expand well. They weren't able to infiltrate into the tumors, and they didn't see the same responses. And what they learned in that trial was T cell exhaustion was a key barrier, and of course, this need for persistence. Lyell specifically sought out technologies to overcome these two barriers, resisting exhaustion and durable stemness. Our first program, as I said, was designed very specifically to overexpress c-Jun to resist exhaustion. Then we also manufacture it with our Epi-R technology to bring about durable stemness. We have prosecuted this in multiple preclinical models showing robust results, including probably one of the most difficult and aggressive non-small cell models, the KP mouse model, which is a syngeneic mouse model with a hostile tumor microenvironment and much better than standard ROR1 CAR T cells. Those that overexpress c-Jun were able to infiltrate the tumors and control the tumors in 50% of the mice, which is this is a model where chemotherapy and checkpoints don't work. Very strong preclinical data in support of this clinical program. Makes sense. Okay, thanks for that. Yeah, let's turn to the TIL program with LYL845. Talk a little bit about what we could see with your initial readout, and maybe how you view the TIL program, you know, versus the, you know, the ROR1 CAR T program, like strategically. Yeah, well, they're both very important cell therapies. I think we all know that Iovance is the first company who's gotten a cell therapy approved for solid tumors with their tumor-infiltrating lymphocyte program, and we've designed ours to be next generation. And as I spoke before, it's manufactured with this Epi-R technology to help make potent T cells that also have durable stemness, so that they can persist over time. We started our program in advanced melanoma because that's where we know TIL work, and we're looking really to bring a more potent, more durable product to the marketplace. And so we're going to be having data in the second half of this year from that program. Primarily, it will be in patients with advanced melanoma, but we have plans also to enroll patients in non-small cell lung cancer and colorectal cancer. Are there lessons to be learned with the development of Iovance's TIL program that you could maybe leverage at LYL? Yes, I think sometimes there's an advantage to being second. Tumor-infiltrating lymphocyte therapy is very complex. For those of you who don't know, you have to harvest a patient's tumor, extract the tumor-infiltrating lymphocytes, expand them from millions to billions of cells, and get reliable and consistent product. And so this is a complex therapy. Took the FDA a while to really figure out how to have adequate oversight over that product, and a long time for Iovance to get that approved. But we've had an opportunity to learn, the regulators have learned, and I think they're very good at working with companies to help move new technologies forward. So I think in our case, it's not only the regulators that have had to learn, but sites. These are complex therapies, and so getting sites set up to have collaboration between cell therapy experts, solid tumor experts, and surgeons who have to harvest the tumor takes some work. And I think those are now really starting to work very, very well, and we can take advantage of the road that was paved, quite frankly, by others. You think FDA understands the subtleties better today than even a few years ago with the different technologies for, you know, not just, you know, CAR Ts, but but TILs as well? Yeah. I mean, the regulators have learned very, very rapidly. I think there's strong leadership at the top, and I think that they are really open to communicating with sponsors and to helping move these technologies forward. They understand they're complex. They regulate them tightly, of course, but I think they are very interested in seeing these novel therapies advance. And I think one of the things that as they do figure out what they want, they're very good at sort of communicating their expectations. Gotcha. Okay. And for 845, you know, help frame kinda what maybe success looks like here with respect to, you know, initial tumor activity? Yeah. So this is gonna be an initial data set. I think it's, The good news with tumor-infiltrating lymphocyte therapy is that, responses typically occur early, and then they generally are durable. We're not gonna have, a tremendous amount of durability data. This is an early data set, but I think what we're looking forward is to be able to show the, a product profile that is competitive with, if differentiated from, that from Iovance. And I think the, the one thing to know about that data set is the standard of care. You know, those patients were enrolled over a very long period of time, and the standard of care in, in melanoma has advanced. More patients are getting treated with checkpoint inhibitors for greater duration of time. So I think our data is more comparable to what they call Cohort Four, so about a 30% or so response rate. Gotcha. And then, the IND for your next gen ROR1, just, just walk us through the steps of that and maybe how you see the differentiation between first and second gen? Yeah. So, Lyell has a second-generation ROR1 CAR T cell program that is expected to enter the clinic soon. We're going to be filing the IND this quarter. And this is a great example of how Lyell is really focused on getting T cell function right, because with our platform technologies, as we get T cell function right, these technologies can be used in any CAR, TIL, or TCR, so great flexibility. And what you see with LYL119, our next ROR1 CAR T cell program, is we're going to be incorporating all four of our technologies. And what we've shown preclinically is that, you know, we have very robust scientists. They've continued to innovate since our first ROR1 CAR T cell program entered the clinic. And this is really a next generation that is significantly more potent and really shows beautiful control of tumors. Just to give you an idea, we have an aggressive non-small cell lung cancer xenograft model, where we can show with our LYL797, very beautiful data. With about 5 million CAR T cells, we can control the tumor and show a benefit to survival. With LYL119, that incorporates all 4 of our technologies, we can control that same tumor with 100,000 CAR T cells. So really a step change in potency as well as durability. So we're very excited to bring that to the clinic. A lower cell count could obviously reduce the risks of, you know, tolerability issues and the like, right? So it can benefit in multiple different ways. Of course, obviously, better tumor infiltration and killing, persistence over time, shorter manufacturing time and obviously, advantages sort of across the board. So one of the things people don't fully appreciate is that ROR1, we believe, is a great target. It's expressed in multiple different tumor types. And so we've shown with our data, 50% in our hands, with our assay, 50% of women with triple-negative breast cancer, about a third of patients with non-small cell lung cancer. But then there are many other tumor types, from ovarian to endometrial, prostate cancer, hematologic malignancies. So a really great target, and as we get T cell function right, we have a lot of flexibility about where we can take these products. Right. And just the breadth of investments that you could make and just for the, you know, just for your next gen on its own, I think could be pretty substantial. Talk a little bit about, you know, how you view partnerships going forward. You know, I mean, obviously, your your assets are wholly owned, but, you know, how do you view kind of the cash and then the investments you need to make to get to that sort of seminal, you know, de-risking event? So I think wholly owned, proprietary, novel technologies, and I think those are all with addressing large populations, all important keywords. But Charlie, you want to talk about our philosophy? Yeah, and, and we're, we're in a great spot from a cash standpoint, as you alluded to. So we have $526 million in cash on the balance sheet, and so that provides us, I think, a lot of flexibility as we think about partnering and when the right time to partner is. So we've just been really focused on executing, being able to build value with our programs, with clinical data. Then obviously, as we get closer to commercialization, I think then we'll begin to think about how do we attack the markets broadly, globally, and, and the-- those could provide opportunities to be able to partner with a commercial partner at some point. But also, Lynn alluded to the fact that our technologies work in any CAR. And so I think as we demonstrate that with our programs, that then opens up the opportunity set for us to be able to partner with other companies as well to incorporate our technologies into their programs. You want to get past that first sort of phase 1 proof of concept first, and then make the decision after. Yeah. Is that it? We're in no rush to enter into a commercial partnership right now. We really want to build that value. We're in a great position with our cash to allow us to do that. If you look at the burn rate that we've had, we're, you know, burning $35 million-$40 million per quarter, with over $500 million cash on the balance sheet. So we feel really good with cash well into 2027 to continue to do that and pick our moment to think about a partner. With manufacturing, you know, that box has been largely checked, which is. It's been largely checked, though, as you may be aware, we did announce a partnership with a company called Cellares that has an automated manufacturing approach. And so that's a proof of concept study that we're doing with them to see if they're able to manufacture our CARs and then provide a really elegant, cost-effective way. It's all automated, cost-effective way to really scale commercials manufacturing as we head towards commercialization. Fantastic! Well, Lynn, Charlie, thank you very much. Thank you. Thank you for the dialogue. Yeah. Nice to see you, and thanks for having us. At Bank of America, I'm pleased to be joined by Sara Kenkare-Mitra. You got it right. President and Head of R&D at Alector. So with that, I'll hand it over to Sara for the presentation. Great. Yeah. Thank you. Thank you, everybody. Firstly, it's a pleasure to be here, and I'm here again, as Alec said, on behalf of Alector. I'm President and Head of R&D. Firstly, we are going to be making some forward-looking statements today, so here are some disclosures, and also please refer to our SEC filing on our websites. Some of you are probably aware, Alector was founded about a decade ago. We have a bold vision, and we had really a passion to harness the brain's immune system to counteract disease in the brain. Our innovative science has fueled a proprietary pipeline of novel immuno-neurology drugs. We have three clinical candidates in advanced stages of development, and we have data readouts anticipated from these candidates, with the imminent one being in Q4 of 2024, and that's the AL002 INVOKE-2 phase II data from early Alzheimer's disease. Additionally, we are well-resourced. We have an experienced team and global partnerships. Today I'm going to talk about our science, our portfolio, and tell you a little bit about our programs. Our science is an integration of insights from human genetics, immunology, and neuroscience. We know that many gene mutations associated with neurodegenerative disease are immune-related. Excuse me. Microglia are the sole immune cell of the brain. Microglia are critical in the functioning of the brain, the health of the brain. They do a number of different critical activities, including sort of cleaning up the debris in the brain, misfolded proteins, looking after the health of the cells of the brain, ensuring that inflammation is resolved, and overall, they are guardians of the brain. Excuse me. So it is this integration of insights between human genetics, immunology, and neuroscience, which is the underpinning of the science behind Alector. You'll see this in every one of our programs, that we are really passionate to utilize these insights into driving our pipeline. As I said earlier, we are well-resourced. We have a pipeline of firsts. We have programs in clinical development. Our progranulin franchise has two monoclonal antibodies, Latozinemab and AL101, both in phase—one in phase III and one in phase II, and I'll tell you more about these later. Latozinemab for the treatment of frontotemporal dementia in the granulin mutations carriers, and AL101 in early Alzheimer's disease. This is a partnership with GSK. Our TREM2 molecule is an agonist of TREM2. It's AL002. I'll dive into this a little deeper later. We have a phase II study, INVOKE-2, in Alzheimer's disease. This is in partnership with AbbVie. Additionally, we have a pipeline of preclinical candidates, and we have our own proprietary blood-brain barrier technology called Alector Brain Carrier, or ABC, that we are utilizing both for novel targets as well as to create second-generation programs. So I'm firstly going to go quickly into the AL002 candidate, particularly because of the real interest in this target. We have imminent data coming in Q4 2024. AL002 is a TREM2 activator. Now, TREM2 is a key signaling receptor on the surface of microglia, and essentially, it senses any damage. It looks for stimuli like apoptotic cells, cellular debris, damage to the myelin sheath, misfolded proteins, et cetera, and regulates microglia survival, proliferation, migration, and function. Additionally, it is also a key genetic risk for AD. Over 40 TREM2 mutations related to AD have been identified, and it's been shown in GWAS studies that elevated TREM2, which reflects a baseline activation of microglia, is associated with slower cognitive decline in Alzheimer's disease. So with that hypothesis, we engineered a molecule, AL002, which was specifically designed and engineered to bind to the stalk region of the TREM2 receptor, which is again on the surface of microglia. Now, by binding the stalk region of the receptor, it ensures that we are not disrupting the natural ligands that bind to the TREM2 receptor, and it activates signaling of that TREM2 receptor downstream. And, this slide merely shows you some of the original preclinical data that you know validated our hypothesis that indeed it binds where it's supposed to bind and that indeed we get TREM2 signaling. Now, initially, we started a phase I study with AL002, which was the molecule had the right pharmacokinetic properties. It was well-tolerated, and we also measured a number of biomarkers to ensure we had target engagement and that we were getting some evidence and hints of microglial activation. On this slide, what I share with you is on the left is dose-dependent reduction of soluble TREM2 in the cerebrospinal fluid, which is associated, again, associating this with target engagement. On the right, you see dose-dependent elevation of CSF1R in the cerebrospinal fluid, which again gives us evidence of microglial activation. Based on those successful data in our phase I study, we then designed our phase II study, which is the INVOKE-2 trial for AL002, again in participants with early Alzheimer's disease. This is the trial that has the readout at the end of this year. So I'm gonna just talk a little bit about the study. It's a randomized, double-blind, placebo-controlled four-arm study with a common close design. This study has three dosing arms, three drug arms, with three different doses. The enrollment for this trial was completed in Q3 of 2023, and we expect data from this study again in Q4 of 2024. We do have a long-term extension. Patients that complete the main study can roll over into the long-term extension. Now, what are we measuring in this study? We have standard clinical and functional outcome measures. Our clinical outcome measure is the CDR sum of boxes, again, similar to the primary endpoint of latozinemab in their phase III trials. We have standard secondary clinical functional outcome measures. And then what we're doing is we're using a proportional analysis that allows us to use the totality of the data because of the crossover design for patients that, you know, are spread across that entirety of the continuum of that study. In addition, this is a very biomarker-rich study. We have biomarkers not only of target engagement, but also of microglial signaling and AD pathology. And what you'll see here reflected on the left is really biomarkers of target engagement and microglial signaling. And then on the right, you have your standard biomarkers of disease pathology, like imaging biomarkers, like amyloid PET, tau PET, as well as plasma and CSF biomarkers, measuring plasma phospho-tau, CSF phospho-tau, plasma A beta 40/42, and a number of other biomarkers. We also have measurements of volumetric MRI in this study. Now, early on in this study, we did see MRI findings that resemble ARIA. And the reason we call it ARIA is because these findings essentially resemble this ARIA that is seen with anti-amyloid therapies in terms of their features on the MRI, the incidence, the timing of onset, the timing of resolution. And in addition, what we found was that initially, the predominant symptomatic ARIA was with patients that were homozygous with the APOE4/E4 alleles. And we voluntarily excluded these patients from our study, and continued on with the non-APOE4/E4 population. And for the most part, that population, we have seen significant reduction in ARIA, and essentially clinically serious cases are uncommon. As I mentioned, this is being done in collaboration with AbbVie, and the AbbVie has an opt-in agreement with us and an option to opt-in, based on the data from this study. I'm gonna move on to the progranulin franchise. We have two molecules here, latozinemab or AL001 and AL101. Both are progranulin-elevating candidates. Now, latozinemab and AL101, again, like all our programs, there's a strong biologic rationale and a genetic rationale, so I'll briefly touch upon both of these. Progranulin is known to be a critical immune regulator, a neuronal survival factor, and a lysosomal chaperone. Now, genetics of progranulin are very well defined. These mutations in progranulin are known to be deleterious. In fact, if you, if you look at the heterozygous of 50% loss of mutation, this is where progranulin levels are reduced to 50% of normal, and that is frontotemporal dementia, particularly with patients with a granulin mutation, the population that we are studying latozinemab in. On the right, you see the mechanism of action of latozinemab and AL101. Both these molecules bind the sortilin receptor, and the sortilin receptor is a degradation receptor that's responsible for degradation of progranulin. By blocking that receptor, you essentially prevent degradation of progranulin and hence leads to elevation of progranulin. We studied this molecule in a standard phase I SAD/MAD trial and found that AL101 had, you know, good pharmacokinetics, well-tolerated, and moved into this phase II study in FTD patients. This was an open-label study, and I want to get your attention to the highlighted arm of the study, which was in symptomatic FTD-GRN patients. And these were dosed. You see the endpoints on the right. We had clinical outcome measures, target engagement, biomarkers of disease activity, and we looked for clinical benefit in these patients. So firstly, we confirmed that, as expected, progranulin was elevated in plasma and CSF to normal levels in normal, healthy volunteers. Additionally, GFAP, a biomarker of astrogliosis, so disease activity, was reduced with treatment in these patients, both in plasma and CSF, down to levels that are seen in asymptomatic carriers of that mutation. Now, this was an open-label study. We did look at the clinical endpoint, but we compared it to historical match controls, essentially from the GENFI cohort. And that allowed us to really get a sense of the impact of treatment of patients with latozinemab. And we were able to show that there is a slowdown of the annual disease progression. As you compare to these historical match controls, that's about 48%. After that, we started our phase 3 pivotal study, which is INFRONT-3, and this study again is evaluating latozinemab in patients with FTD-GRN. We have 103 symptomatic patients and 16 at-risk carriers in this study. This study completed enrollment in Q4 of 2023. It has a 96-week treatment period. It has all the standard assessments, primary endpoint of CDR plus NACC FTLD sum of boxes, secondary clinical outcomes, and exploratory endpoints that are both imaging as well as soluble biomarkers. Now, AL101, the second program, is being developed to align to the needs of the broader population, like in Alzheimer's disease. Again, underpinnings are genetic and biological. The genetics of progranulin deficiency are strong in Alzheimer's disease, and from a biology perspective, we've shown in disease models that ablation of progranulin exacerbates AD, while overexpression is protective in AD. Now, this program completed phase I in healthy volunteers. We now started a phase II study, PROGRESS-AD, which is being operationalized by our partner, GSK. The enrollment is ongoing in this study. It was initiated in February of 2024. This is the design of the PROGRESS-AD study. Again, a very standard phase II study, a randomized, double-blind, placebo-controlled study, which is looking at efficacy and safety in patients with early Alzheimer's disease. We have two dose levels in this study. The primary, secondary endpoints are again very similar to the ones I've shown you with AL002. The biomarkers are imaging and soluble biomarkers. Again, both these programs, these candidates are being developed in partnership with GSK. So with that, I just wanna end reminding you that Alector is pioneering immuno-neurology. We have a number of firsts. We have three clinical candidates in advanced stages of development, and data anticipated in Q4 2024 with AL002, our TREM2 activating candidate. Thank you.